This panel provides drug-protein interaction and their ADRs along with references
| Toxicity |
Interacting Protein |
Mechanism |
Reference |
| Abnormal Axial Rotation | p-aminophenol (PAP) (P00042) | P-aminophenol (PAP) and 7-hydroxyaminofluorene (7-OH-AF), were embryotoxic at concentrations 10-fold lower than the corresponding acetylated compounds,each produced a greater incidence of abnormal axial rotation and a greater decrease in embryonic protein than APAP or 7-OH-AAF In addition, the embryos exposed to PAP or 7-OH-AF were morphologically and histologically dissimilar to those exposed to the acetylated compounds [ ADR Type 1 ] | Modulation of the embryotoxicity and cytotoxicity elicited by 7-hydroxy-2-acetylaminofluorene and acetaminophen via deacetylation
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| Apap-Mediated Toxicity In Human Hepatocytes | UDP-glucuronosyltransferase 1-6 (P19224) | The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes;The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital;This synergistic increase in toxicity is postulated to be due to inhibition of UGTs [ ADR Type 4 ] | Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15 Potential implications in acetaminophen-induced hepatotoxicity
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| Chronic Hypoxia | Sulfotransferase family cytosolic (O43704) | Decreases in microsomal UDP-glucuronosyltransferase and cytosolic Sulfotransferase activities were found in livers of animals exposed to chronic hypoxia [ ADR Type 2 ] | Effect of chronic hypoxia on acetaminophen metabolism in the rat
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| Hemolysis | Glucose-6-phosphate 1-dehydrogenase (P11413) | Patients with glucose-6-phosphate dehydrogenase deficiency who overdose with acetaminophen should be monitored for the possible development of subsequent drug-induced hemolysis [ ADR Type 3 ] | Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency
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| Hemolysis | Haptoglobin (P00738) | Hemoglobin on presentation was 14 g/dL and reached a nadir of 9.4 g/dL on admission day 4,suggesting that Patients with glucose-6-phosphate dehydrogenase deficiency who overdose with acetaminophen should be monitored for the possible development of subsequent drug-induced hemolysis. [ ADR Type 3 ] | Hemolysis after acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency
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| Hepatic Injury | Alpha-2A adrenergic receptor (P08913) | Acetaminophen is potentiated by alpha(1)-adrenoreceptor aGOnists@creating the potential for increased susceptibility to hepatic injury [ ADR Type 2 ] | Adrenergic modulation of hepatotoxicity
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| Hepatotoxicity | Alanine aminotransferase (P24298) | Acetaminophen-induced hepatotoxicity [ ADR Type 1 ] | Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice
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| Hepatotoxicity | Alkaline phosphatase (P05186) | Elevation of alkaline phosphatase leads to severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. [ ADR Type 4 ] | Acetaminophen hepatotoxicity augmented by zidovudine
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| Hepatotoxicity | Caspase recruitment domain-containing protein (Q9BWT7) | Xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. [ ADR Type 1 ] | Toxicology Protecting liver from painkiller's lethal dose
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| Hepatotoxicity | Cytochrome P450 1A2 (P05177) | Particularly at high doses@ cytochrome P-450 enzymes--especially CYP1A2@ CYP2E1@ and isoforms of CYP3A--convert APAP to a reactive quinone form@ N-acetyl-p-benzoquinone imine (NAPQI)@that covalently binds to cellular macromolecules and also causes production of reactive oxygen species@ and leads to acetaminophen-induced hepatotoxicity. [ ADR Type 1 ] | Toxicology Protecting liver from painkiller's lethal dose
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| Hepatotoxicity | Cytochrome P450 2E1 (P05181) | Particularly at high doses@ cytochrome P-450 enzymes--especially CYP1A2@ CYP2E1@ and isoforms of CYP3A--convert APAP to a reactive quinone form@ N-acetyl-p-benzoquinone imine (NAPQI)@that covalently binds to cellular macromolecules and also causes production of reactive oxygen species@ and leads to acetaminophen-induced hepatotoxicity [ ADR Type 1 ] | Toxicology Protecting liver from painkiller's lethal dose
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| Hepatotoxicity | Cytochrome P450 3A4 (P08684) | Particularly at high doses@ cytochrome P-450 enzymes--especially CYP1A2@ CYP2E1@ and isoforms of CYP3A--convert APAP to a reactive quinone form@ N-acetyl-p-benzoquinone imine (NAPQI)@that covalently binds to cellular macromolecules and also causes production of reactive oxygen species@ and leads to acetaminophen-induced hepatotoxicity. [ ADR Type 1 ] | Toxicology Protecting liver from painkiller's lethal dose
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| Hepatotoxicity | Na+/K+-ATPase (P00034) | Early inhibition of the Na+/K+-ATPase leads to acetaminophen-induced hepatotoxicity. [ ADR Type 2 ] | Early inhibition of the Na+/K+-ATPase ion pump during acetaminophen-induced hepatotoxicity in rat
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| Hepatotoxicity | Ornithine decarboxylase (P11926) | Liver ornithine decarboxylase (ODC) activity@ which reflects the earliest phases of cell multiplication@During the next 12 hours@decreased by 60% to 70% and cellular necrosis became evident@and reached a peak at 24 to 36 hours.So organelles may play a critical role in acetaminophen hepatotoxicity. [ ADR Type 2 ] | Acetaminophen liver injury: sequential changes in two biochemical indices of regeneration and their relationship to histologic alterations
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| Hepatotoxicity | Transcription factor AP-1 (P05412) | AP-1 transcription factor and Fos-related antigens (fra) as well as Jun proteins are associated in the hepatotoxic response of liver to APAP and may serve as useful molecular biomarkers for chemical-induced hepatotoxicity. [ ADR Type 2 ] | Acetaminophen-induced hepatotoxicity is associated with early changes in AP-1 DNA binding activity
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| Hepatotoxicity | Transforming protein v-Fos/v-Fox (P29176) | AP-1 transcription factor and Fos-related antigens (fra) as well as Jun proteins are associated in the hepatotoxic response of liver to APAP and may serve as useful molecular biomarkers for chemical-induced hepatotoxicity [ ADR Type 2 ] | Acetaminophen-induced hepatotoxicity is associated with early changes in AP-1 DNA binding activity
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| Hepatotoxin-Induced Effects | Beta-glucuronidase (P08236) | Acetaminophen markedly decreased biliary concentrations and efflux rates of beta-NAG and beta-GLUC in Fischer-344 rats@suggesting that the hepatotoxin-induced effects on biliary iron excretion may be mediated through effects on lysosomal exocytosis. [ ADR Type 2 ] | Biliary excretion of lysosomal enzymes, iron, and oxidized protein in Fischer-344 and Sprague-Dawley rats and the effects of diquat and acetaminophen
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| Hepatotoxin-Induced Effects | Beta-N-acetylglucosaminidase (P39848) | Acetaminophen markedly decreased biliary concentrations and efflux rates of beta-NAG and beta-GLUC in Fischer-344 rats@suggesting that the hepatotoxin-induced effects on biliary iron excretion may be mediated through effects on lysosomal exocytosis. [ ADR Type 2 ] | Biliary excretion of lysosomal enzymes, iron, and oxidized protein in Fischer-344 and Sprague-Dawley rats and the effects of diquat and acetaminophen
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| Hyperglycemia | Glutamate pyruvate transaminase (Q28DB5) | Fasted animals showed a dramatic INCREASE in susceptibility to acetaminophen-induced hepatotoxicity as measured by increased SGPT levels@SUGGESTING Acetaminophen-INDUCED hepatic glycogen depletion and hyperglycemia in mice [ ADR Type 2 ] | Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice
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| Hypoxia | microsomal UDP-glucuronosyltransferase (Q29566) | Decreases in microsomal UDP-glucuronosyltransferase and cytosolic Sulfotransferase activities were found in livers of animals exposed to chronic hypoxia. [ ADR Type 2 ] | Effect of chronic hypoxia on acetaminophen metabolism in the rat
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| Liver Necrosis | Sulfotransferase (P50225) | Enhanced the Vmax of acetaminophen Sulfotransferase activity leads to acetaminophen-induced liver necrosis. [ ADR Type 2 ] | Relationship between sulfotransferase activity and susceptibility to acetaminophen-induced liver necrosis in the hamster
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| Renal Functional Changes | 7-ethoxycoumarin O-deethylase (O23976) | Kidneys from F344 rats displayed greater concentrations of P-450 and greater ethoxycoumarin-o-deethylase activity than kidneys from SD rats,reflecting APAP-induced renal functional changes. [ ADR Type 1 ] | Acetaminophen nephrotoxicity in the rat I Strain differences in nephrotoxicity and metabolism
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| Renal Functional Changes | Cytochrome P450 (P15538) | APAP-induced renal functional changes(elevation in blood urea nitrogen and reduction in the accumulation of p-aminohippurate by renal cortical slices) also correlated with strain-dependent histopathological changes. Such strain differences have been attributed to differences in renal P-450 activation of APAP or the deacetylation of APAP to the nephrotoxic metabolite@ p-aminophenol (PAP). [ ADR Type 1 ] | Acetaminophen nephrotoxicity in the rat I Strain differences in nephrotoxicity and metabolism
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| Respiratory Burst | Myeloperoxidase precursor (P05164) | Myeloperoxidase appears to be much more important in the binding of acetaminophen to DNA than it is in the DNA binding of arylamines in general@causing the respiratory burst the bioactivation of certain arylamines [ ADR Type 2 3 ] | Metabolic activation and nucleic acid binding of acetaminophen and related arylamine substrates by the respiratory burst of human granulocytes
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| Sleepy | Cytochrome P450 2E1 (P05181) | Isoniazid inhibits CYP2E1 activity@ thus it increases the level of acetaminophen in blood and increases acetaminophen toxicity [ ADR Type 4 ] | Acetaminophen hepatotoxicity: potentiation by isoniazid
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| Toxicity In Human Hepatocytes | UDP-glucuronosyltransferase (P22309) | The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes;The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital;This synergistic increase in toxicity is postulated to be due to inhibition of UGTs. [ ADR Type 4 ] | Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15 Potential implications in acetaminophen-induced hepatotoxicity
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| Toxicity In Human Hepatocytes | UDP-glucuronosyltransferase 1-6 (P19224) | The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes;The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital;This synergistic increase in toxicity is postulated to be due to inhibition of UGTs [ ADR Type 4 ] | Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15 Potential implications in acetaminophen-induced hepatotoxicity
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| Toxicity In Human Hepatocytes | UDP-glucuronosyltransferase 1-9 (O60656) | The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes;The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital;This synergistic increase in toxicity is postulated to be due to inhibition of UGTs. [ ADR Type 4 ] | Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15 Potential implications in acetaminophen-induced hepatotoxicity
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| Toxicity In Human Hepatocytes | UDP-glucuronosyltransferase 2B15 precursor (P54855) | The inhibition of APAP glucuronidation by phenobarbital leads to an increase in APAP-mediated toxicity in human hepatocytes; The toxicity to hepatocytes was further increased by coadministering APAP with phenytoin and phenobarbital;This synergistic increase in toxicity is postulated to be due to inhibition of UGTs. [ ADR Type 4 ] | Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15 Potential implications in acetaminophen-induced hepatotoxicity
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